- SARS-CoV-2 NSP13 suppresses the Hippo pathway downstream effector YAP -
The Hippo pathway plays critical roles in tissue development, regeneration, and immune homeostasis. The widespread pandemic of Coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 has resulted in a global healthcare crisis and strained health resources. How SARS-CoV-2 affects Hippo signaling in host cells has remained poorly understood. Here, we report that SARS-CoV-2 infection in patient lung cells and cardiomyocytes derived from human induced pluripotent stem cells (iPS-CMs) suppressed YAP target gene expression, as evidenced by RNA sequencing data. Furthermore, in a screening of nonstructural proteins from SARS-CoV-2, nonstructural protein 13 (NSP13) significantly inhibited YAP transcriptional activity independent of the YAP upstream suppressor kinase Lats1/2. Consistent with this, NSP13 suppressed active YAP (YAP5SA) in vivo, whereby NSP13 expression reverted the phenotype of YAP5SA transgenic mice. From a mechanistic standpoint, NSP13 helicase activity was shown to be required for its suppression of YAP. Furthermore, through the interaction of NSP13 with TEAD4, which is the most common YAP-interacting transcription factor in the nucleus, NSP13 recruited endogenous YAP suppressors such as CCT3 and TTF2 to inactivate the YAP/TEAD4 complex. These findings reveal the function and mechanism of the SARS-CoV-2 helicase NSP13 in host cells and partially explain the toxic effect of SARS-CoV-2 in particular host tissue with high YAP activity.
- Gut Microbiome Dynamics and Predictive Value in Hospitalized COVID-19 Patients: A Comparative Analysis of Shallow and Deep Shotgun Sequencing -
The COVID-19 pandemic caused by SARS-CoV-2 has led to a wide range of clinical presentations, with respiratory symptoms being common. However, emerging evidence suggests that the gastrointestinal (GI) tract is also affected, with angiotensin-converting enzyme 2, a key receptor for SARS-CoV-2, abundantly expressed in the ileum and colon. The virus has been detected in GI tissues and fecal samples, even in cases with negative respiratory results. GI symptoms have been associated with an increased risk of ICU admission and mortality. The gut microbiome, a complex ecosystem of around 40 trillion bacteria, plays a crucial role in immunological and metabolic pathways. Dysbiosis of the gut microbiota, characterized by a loss of beneficial microbes and decreased microbial diversity, has been observed in COVID-19 patients, potentially contributing to disease severity. We conducted a comprehensive gut microbiome study in 204 hospitalized COVID-19 patients using both shallow and deep shotgun sequencing methods. We aimed to track microbiota composition changes induced by hospitalization, link these alterations to clinical procedures (antibiotics administration) and outcomes (ICU referral, survival), and assess the predictive potential of the gut microbiome for COVID-19 prognosis. Shallow shotgun sequencing was evaluated as a cost-effective diagnostic alternative for clinical settings.
- Persistent immune imprinting after XBB.1.5 COVID vaccination in humans -
Immune imprinting - also known as original antigenic sin describes how the first exposure a virus shapes the immunological outcome of subsequent exposures to antigenically related strains. SARS-CoV-2 Omicron breakthrough infections and bivalent COVID-19 vaccination were shown to primarily recall cross-reactive memory B cells and antibodies induced by prior mRNA vaccination with the Wuhan-Hu-1 spike rather than priming naive B cells that recognize Omicron-specific epitopes. These findings underscored a strong immune imprinting resulting from repeated Wuhan-Hu-1 spike exposures. To understand if immune imprinting can be overcome, we investigated memory and plasma antibody responses after administration of the updated XBB.1.5 COVID mRNA vaccine booster. Our data show that the XBB.1.5 booster elicits neutralizing antibody responses against current variants that are dominated by recall of pre-existing memory B cells previously induced by the Wuhan-Hu-1 spike. These results indicate that immune imprinting persists even after multiple exposures to Omicron spikes through vaccination and infection, including post XBB.1.5 spike booster mRNA vaccination, which will need to be considered to guide the design of future vaccine boosters.
- Antiviral humoral immunity against SARS-CoV-2 Omicron subvariants induced by XBB.1.5 monovalent vaccine in infection-naive and XBB-infected individuals -
To control infection with SARS-CoV-2 Omicron XBB subvariants, the XBB.1.5 monovalent mRNA vaccine has been available since September 2023. However, we have found that natural infection with XBB subvariants, including XBB.1.5, does not efficiently induce humoral immunity against the infecting XBB subvariants. These observations raise the possibility that the XBB.1.5 monovalent vaccine may not be able to efficiently induce humoral immunity against emerging SARS-CoV-2 variants, including a variety of XBB subvariants (XBB.1.5, XBB.1.16, XBB.2.3, EG.5.1 and HK.3) as well as BA.2.86. To address this possibility, we collected two types of sera from individuals vaccinated with the XBB.1.5 vaccine; those who had not been previously infected with SARS-CoV-2 and those who had been infected with XBB subvariants prior to XBB.1.5 vaccination. We collected sera before and 3-4 weeks after vaccination, and then performed a neutralization assay using these sera and pseudoviruses.
- Mechanistic insights into ligand dissociation from the SARS-CoV-2 spike glycoprotein -
The COVID-19 pandemic, driven by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has spurred an urgent need for effective therapeutic interventions. The spike glycoprotein of the SARS-CoV-2 is crucial for infiltrating host cells, rendering it a key candidate for drug development. By interacting with the human angiotensin-converting enzyme 2 (ACE2) receptor, the spike initiates the infection of SARS-CoV-2. Linoleate is known to bind the spike glycoprotein, subsequently reducing its interaction with ACE2. However, the detailed kinetics underlying the protein-ligand interaction remains unclear. In this study, we characterized the pathways of ligand dissociation and the conformational changes associated with the spike glycoprotein by using ligand Gaussian accelerated molecular dynamics (LiGaMD). Our simulations resulted in eight complete ligand dissociation trajectories, unveiling two distinct ligand unbinding pathways. The preference between these two pathways depends on the gate distance between two -helices in the receptor binding domain (RBD) and the position of the N-linked glycan at N343. Our study also highlights the essential contributions of K417, N121 glycan, and N165 glycan in ligand unbinding, which are equally crucial in enhancing spike-ACE2 binding. We suggest that the presence of the ligand influences the motions of these residues and glycans, consequently reducing accessibility for spike-ACE2 binding. These findings enhance our understanding of ligand dissociation from the spike glycoprotein and offer significant implications for drug design strategies in the battle against COVID-19.
- Generalizable features for the diagnosis of infectious disease, autoimmunity and cancer from adaptive immune receptor repertoires -
Adaptive immune receptor repertoires (AIRRs) have emerged as promising biomarkers for disease diagnosis and clinical prognosis. However, their high diversity and limited sharing between donors pose unique challenges when employing them as features for machine learning based diagnostics. In this study, we investigate the commonly used approach of representing each receptor as a member of a "clonotype cluster". We then construct a feature vector for each donor from clonotype cluster frequencies (CCFs). We find that CCFs are sparse features and that classifiers trained on them do not generalize well to new donors. To overcome this limitation, we introduce a novel approach where we transform cluster frequencies using an adjacency matrix built from pairwise similarities of all receptors. This transformation produces a new feature, termed paratope cluster occupancies (PCOs). Leveraging publicly available AIRR datasets encompassing infectious diseases (COVID-19, HIV), autoimmune diseases (autoimmune hepatitis, type 1 diabetes), and cancer (colorectal cancer, non-small cell lung cancer), we demonstrate that PCOs exhibit lower sparsity compared to CCFs. Furthermore, we establish that classifiers trained on PCOs exhibited improved generalizability and overall classification performance (median ROC AUC 0.893) when compared to CCFs (median ROC AUC 0.714) over the six diseases. Our findings highlight the potential of utilizing PCOs as a feature representation for AIRR analysis in diverse disease contexts.
- Human Cytokine and Coronavirus Nucleocapsid Protein Interactivity Using Large-Scale Virtual Screens -
In the battle against the ever-changing SARS-CoV-2 landscape, understanding the interactions between viral proteins and the human immune system is paramount as it helps to explain potential factors contributing to diverse immunological responses in infected individuals. In this study, we employed state-of-the-art molecular docking tools to conduct large-scale virtual screens, predicting the binding affinities between 64 human cytokines against 17 coronavirus nucleocapsid proteins. Our comprehensive in silico analyses reveal specific changes in cytokine-nucleocapsid protein interactions, shedding light on potential modulators of the host immune response during infection. These findings offer valuable insights into the molecular mechanisms underlying viral pathogenesis and may guide the future development of targeted interventions. This manuscript serves as insight into the comparison of deep learning based AlphaFold2-Multimer and the semi-physicochemical based HADDOCK for protein-protein docking. We show the two methods are complementary in their predictive capabilities. We also introduce a novel algorithm for rapidly assessing the binding interface of protein-protein docks using graph edit distance: graph-based residue assessment function (G-RAF). The high-performance computational framework presented here will not only aid in accelerating the discovery of effective interventions against emerging viral threats, but extend to other applications of high throughput protein-protein screens.
- Mechanism-based classification of SARS-CoV-2 Variants by Molecular Dynamics Resembles Phylogenetic Tree -
The COVID-19 pandemics has demonstrated the vulnerability of our societies to viral infectious disease. The mitigation of COVID-19 was complicated by the emergence of Variants of Concern (VOCs) with varying properties including increased transmissibility and immune evasion. Traditional population sequencing proved to be slow and not conducive for timely action. To tackle this challenge, we introduce the Persistence Score (PS) that assesses the pandemic potential of VOCs based on molecular dynamics of the interactions between the SARS-CoV-2 Receptor Binding Domain (RBD) and the ACE2 residues. Our mechanism-based classification approach successfully grouped VOCs into clinically relevant subgroups with higher sensitivity than classical affinity estimations and allows for risk assessment of hypothetical new VOCs. The PS-based interaction analysis across VOCs resembled the phylogenetic tree of SARS-Cov-2 demonstrating its predictive relevance for pandemic preparedness. Thus, PS allows for early detection of a variant's pandemic potential, and an early risk evaluation for data-driven policymaking.
- Functional and antigenic characterization of SARS-CoV-2 spike fusion peptide by deep mutational scanning -
The fusion peptide of SARS-CoV-2 spike protein is functionally important for membrane fusion during virus entry and is part of a broadly neutralizing epitope. However, sequence determinants at the fusion peptide and its adjacent regions for pathogenicity and antigenicity remain elusive. In this study, we performed a series of deep mutational scanning (DMS) experiments on an S2 region spanning the fusion peptide of authentic SARS-CoV-2 in different cell lines and in the presence of broadly neutralizing antibodies. We identified mutations at residue 813 of the spike protein that reduced TMPRSS2-mediated entry with decreased virulence. In addition, we showed that an F823Y mutation, present in bat betacoronavirus HKU9 spike protein, confers resistance to broadly neutralizing antibodies. Our findings provide mechanistic insights into SARS-CoV-2 pathogenicity and also highlight a potential challenge in developing broadly protective S2-based coronavirus vaccines.
- copepodTCR: Identification of Antigen-Specific T Cell Receptors with combinatorial peptide pooling -
T cell receptor (TCR) repertoire diversity enables the orchestration of antigen-specific immune responses against the vast space of possible pathogens. Identifying TCR/antigen binding pairs from the large TCR repertoire and antigen space is crucial for biomedical research. Here, we introduce copepodTCR, an open-access tool for the design and interpretation of high-throughput experimental assays to determine TCR specificity. copepodTCR implements a combinatorial peptide pooling scheme for efficient experimental testing of T cell responses against large overlapping peptide libraries, useful for "deorphaning" TCRs of unknown specificity. The scheme detects experimental errors and, coupled with a hierarchical Bayesian model for unbiased results interpretation, identifies the response-eliciting peptide for a TCR of interest out of hundreds of peptides tested using a simple experimental set-up. We experimentally validated our approach on a library of 253 overlapping peptides covering the SARS-CoV-2 spike protein. We provide experimental guides for efficient design of larger screens covering thousands of peptides which will be crucial for the identification of antigen-specific T cells and their targets from limited clinical material.
- Reasons for not getting vaccinated against COVID-19 in German-speaking Switzerland: An online survey among vaccine hesitant 16-60 year olds -
Background: Several research studies have examined the reasons why people are hesitant to be vaccinated against COVID-19. However, there is no published data to date on Switzerland. Identifying these reasons among the Swiss population who are vaccine hesitant may help inform campaigns to encourage vaccine confidence. Aims: The primary aim of this study is to identify the reasons for not getting vaccinated against COVID-19 among Swiss residents who are vaccine hesitant. The secondary aim is to examine whether reasons differ by age, gender, education, and likelihood of accepting a vaccination to better target campaigns and design interventions. Design: An online survey asked participants to indicate the reasons why they were hesitant to be vaccinated against COVID-19. Setting: German-speaking Swiss Cantons, the survey was administered online between 5 May 2021 and 16 May 2021. Participants: The participants in this analysis were a sample of (N=1191) Swiss residents age 16-60 years old from German-speaking Cantons, who could answer an online survey in German, who had yet not been vaccinated, who had not yet registered for a vaccination appointment, and who did not indicate that they would definitely be vaccinated if offered the chance. Findings: Among people who are vaccine hesitant in Switzerland, the most common reasons for being hesitant were side-effect, safety, and effectiveness concerns. It was also common for people to indicate that they were healthy/at low risk, would decide later, and that they wanted to build immunity naturally. Less common, but still prevalent concerns included wanting more information, thinking COVID-19 was not a real threat, and concerns that the vaccine may serve another purpose. Differences in reasons for being vaccine hesitant were found by age, gender, education, and likelihood of accepting a vaccination if offered. Conclusions: To increase the likelihood of accepting a vaccination, vaccination campaigns should address side-effect, safety, and effectiveness concerns. Campaigns could also consider informing people why it is necessary for people in lower risk groups to be vaccinated, and why vaccination is preferable to infection for building immunity. While campaigns may be effective in reaching some of the population, alternative strategies might be necessary to strengthen the trust relationship with vaccines and vaccine providers in some groups. Less prevalent concerns, such as not liking needles, could be addressed through individual level interventions.
- Expression and fusogenic activity of SARS CoV-2 Spike protein displayed in the HSV-1 Virion. -
Severe acute respiratory syndrome coronavirus (SARS-CoV) is a zoonotic pathogen that can cause severe respiratory disease in humans. The new SARS-CoV-2 is the cause of the current global pandemic termed coronavirus disease 2019 (COVID-19) that has resulted in many millions of deaths world-wide. The virus is a member of the Betacoronavirus family, its genome is a positive strand RNA molecule that encodes for many genes which are required for virus genome replication as well as for structural proteins that are required for virion assembly and maturation. A key determinant of this virus is the Spike (S) protein embedded in the virion membrane and mediates attachment of the virus to the receptor (ACE2). This protein also is required for cell-cell fusion (syncytia) that is an important pathogenic determinant. We have developed a pseudotyped herpes simplex virus type 1 (HSV-1) recombinant virus expressing S protein in the virion envelop. This virus has also been modified to express a Venus fluorescent protein fusion to VP16, a virion protein of HSV-1. The virus expressing Spike can enter cells and generates large multi-nucleated syncytia which are evident by the Venus fluorescence. The HSV-1 recombinant virus is genetically stable and virus amplification can be easily done by infecting cells. This recombinant virus provides a reproducible platform for Spike function analysis and thus adds to the repertoire of pseudotyped viruses expressing Spike.
- Streamlining Computational Fragment-Based Drug Discovery through Evolutionary Optimization Informed by Ligand-Based Virtual Prescreening -
Recent advancements in computational methods provide the promise of dramatically accelerating drug discovery. While mathematical modeling and machine learning have become vital in predicting drug-target interactions and properties, there is untapped potential in computational drug discovery due to the vast and complex chemical space. This paper advances a novel computational fragment-based drug discovery (FBDD) method called Fragments from Ligands Drug Discovery (FDSL-DD), which aims to streamline drug design by applying a two-stage optimization process informed by machine learning and evolutionary principles. In this approach, in silico screening identifies ligands from a vast library, which are then fragmentized while attaching specific attributes based on predicted binding affinity and interaction with the target sub-domain. This process both shrinks the search space and focuses on promising regions within it. The first optimization stage assembles these fragments into larger compounds using evolutionary strategies, and the second stage iteratively refines resulting compounds for enhanced bioactivity. The methodology is validated across three diverse protein targets involved in human solid cancers, bacterial antimicrobial resistance, and SARS-CoV-2 viral entry, demonstrating the approach's broad applicability. Using the proposed FDSL-DD and two-stage optimization approach yields high-affinity ligand candidates more efficiently than other state-of-the-art computational methods. Furthermore, a multiobjective optimization is presented that accounts for druglikeness while still producing potential candidate ligands with high binding affinity. In conclustion, the results demonstrate that integrating detailed chemical information with a constrained search framework can markedly optimize the initial drug discovery process, offering a more precise and efficient route to developing new therapeutics.
- Epitope mapping of SARS-CoV-2 RBDs by hydroxyl radical protein footprinting reveals the importance of including negative antibody controls. -
Understanding protein-protein interaction is essential when designing drugs or investigating biological processes. A variety of techniques can be employed in order to map the regions on proteins that are involved in binding eg., CryoEM, X-ray spectroscopy, linear epitope mapping, or mass spectrometry-based methods. The most commonly utilized mass spectrometry-based techniques are cross-linking and hydrogen-deuterium exchange (HDX). An alternative technique for identifying residues on the three-dimensional structure of proteins, that are involved in binding, can be hydroxyl radical protein footprinting (HRPF). However, this method is currently hampered by high initial cost and complex experimental setup. Here we set out to present a generally applicable method using Fenton chemistry for mapping of epitopes in a standard mass spectrometry laboratory. Furthermore, the described method illustrates the importance of controls on several levels when performing mass spectrometry-based epitope mapping. In particular, the inclusion of a negative antibody control has not previously been widely utilized in epitope mapping by HRPF analysis. In order to limit the number of false positives, we further introduced quantification by TMT labelling, thereby allowing for direct comparison between sample conditions and biological triplicates. Lastly, up to six technical replicates were incorporated in the experimental setup in order to achieve increased depth of the final analysis. Both binding and opening of regions on receptor-binding domain (RBD) from SARS-CoV-2 Spike Protein, Alpha and Delta variants, were observed. The negative control antibody experiment combined with the high overlap between biological triplicates resulted in the exclusion of 40% of the significantly changed regions, including both binding and opening regions. The final identified binding region was mapped to a three-dimensional structure and agrees with the literature for neutralizing antibodies towards SARS-CoV-2 Spike Protein. The presented method is straightforward to implement for the analysis of HRPF in a generic MS-based laboratory. The high reliability of the data was achieved by increasing the number of technical and biological replicates combined with negative antibody controls.
- Generation and evaluation of protease inhibitor-resistant SARS-CoV-2 strains -
Since the start of the SARS-CoV-2 pandemic, the search for antiviral therapies has been at the forefront of medical research. To date, the 3CLpro inhibitor nirmatrelvir (Paxlovid) has shown the best results in clinical trials and the greatest robustness against variants. A second SARS-CoV-2 protease inhibitor, ensitrelvir (Xocova), has been developed. Ensitrelvir, currently in Phase 3, was approved in Japan under the emergency regulatory approval procedure in November 2022, and is available since March 31, 2023. One of the limitations for the use of antiviral monotherapies is the emergence of resistance mutations. Here, we experimentally generated mutants resistant to nirmatrelvir and ensitrelvir in vitro following repeating passages of SARS-CoV-2 in the presence of both antivirals. For both molecules, we demonstrated a loss of sensitivity for resistance mutants in vitro. Using a Syrian golden hamster infection model, we showed that the ensitrelvir M49L mutation confers a high level of in vivo resistance. Finally, we identified a recent increase in the prevalence of M49L-carrying sequences, which appears to be associated with multiple repeated emergence events in Japan and may be related to the use of Xocova in the country since November 2022. These results highlight the strategic importance of genetic monitoring of circulating SARS-CoV-2 strains to ensure that treatments administered retain their full effectiveness.
Effect of Metformin in Reducing Fatigue in Long COVID in Adolescents - Conditions: Long COVID
Interventions: Drug: Metformin; Other: Placebo
Sponsors: Trust for Vaccines and Immunization, Pakistan
Not yet recruiting
A Randomized Trial Evaluating a mRNA VLP Vaccine’s Immunogenicity and Safety for COVID-19 - Conditions: COVID-19; SARS-CoV-2 Infection
Interventions: Biological: AZD9838; Biological: Licensed mRNA vaccine
Sponsors: AstraZeneca
Not yet recruiting
“The Effect of Aerobic Exercise and Strength Training on Physical Activity Level, Quality of Life and Anxiety-Stress Disorder in Young Adults With and Without Covid-19” - Conditions: COVID-19
Interventions: Behavioral: Aerobic Exercise and Strength Training
Sponsors: Pamukkale University
Active, not recruiting
Safety Study of SLV213 for the Treatment of COVID-19. - Conditions: COVID-19
Interventions: Other: Placebo for SLV213; Drug: SLV213
Sponsors: National Institute of Allergy and Infectious Diseases (NIAID)
Not yet recruiting
Vale+Tú Salud: Corner-Based Randomized Trial to Test a Latino Day Laborer Program Adapted to Prevent COVID-19 - Conditions: COVID-19
Interventions: Behavioral: COVID-19 Group Problem Solving; Behavioral: Standard of Care; Behavioral: Booster session
Sponsors: The University of Texas Health Science Center, Houston; National Institute on Minority Health and Health Disparities (NIMHD)
Recruiting
Collection of Additional Biological Samples From Potentially COVID-19 Patients for Monitoring of Biological Parameters Carried Out as Part of the Routine - Conditions: SARS CoV 2 Infection
Interventions: Diagnostic Test: RIPH2
Sponsors: CerbaXpert
Not yet recruiting
Promoting Engagement and COVID-19 Testing for Health - Conditions: COVID-19
Interventions: Behavioral: COVID-19 Test Reporting; Behavioral: Personalized Nudges via Text Messaging; Behavioral: Non-personalized Nudges via Text Messaging
Sponsors: Emory University; National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); Morehouse School of Medicine; Georgia Institute of Technology
Not yet recruiting
Performance Evaluation of the Lucira COVID-19 & Flu Test - Conditions: COVID-19; Influenza
Interventions: Device: Lucira COVID-19 & Flu Test
Sponsors: Lucira Health Inc
Completed
Development and Qualification of Methods for Analyzing the Mucosal Immune Response to COVID-19 - Conditions: Certain Disorders Involving the Immune Mechanism
Interventions: Biological: Sampling; Biological: PCR (polymerase chain reaction) SARS-CoV-2
Sponsors: University Hospital, Tours
Not yet recruiting
Efficacy of Two Therapeutic Exercise Modalities for Patients With Persistent COVID - Conditions: Persistent COVID-19
Interventions: Other: exercise programe
Sponsors: Facultat de ciencies de la Salut Universitat Ramon Llull
Recruiting
Mitigating Mental and Social Health Outcomes of COVID-19: A Counseling Approach - Conditions: Social Determinants of Health; Mental Health Issue; COVID-19
Interventions: Behavioral: Individual counseling; Behavioral: Group counseling; Other: Resources
Sponsors: Idaho State University
Not yet recruiting
Water-based Activity to Enhance Recovery in Long COVID - Conditions: Long COVID
Interventions: Behavioral: WATER+CT; Behavioral: Usual Care
Sponsors: VA Office of Research and Development
Not yet recruiting
Robotic Assisted Hand Rehabilitation Outcomes in Adults After COVID-19 - Conditions: Robotic Exoskeleton; Post-acute Covid-19 Syndrome; Rehabilitation Outcome; Physical And Rehabilitation Medicine
Interventions: Device: Training with a Robotic Hand Exoskeleton
Sponsors: University of Valladolid; Centro Hospitalario Padre Benito Menni
Completed
Cognitive Rehabilitation in Post-COVID-19 Syndrome - Conditions: Post-COVID-19 Syndrome
Interventions: Behavioral: CO-OP Procedures; Behavioral: Inactive Control Group
Sponsors: University of Missouri-Columbia; Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Not yet recruiting
Implementing PCR testing in general practice-a qualitative study using normalization process theory - CONCLUSION: In its current form, the added diagnostic value of using POC PCR testing in general practice was not sufficient for the professionals to justify the increased work connected to the usage of the diagnostic procedure in daily practice.
Inhibition of bradykinin in SARS-CoV-2 infection: a randomised, double-blind trial of icatibant compared with placebo (ICASARS) - SARS-CoV-2 binds to ACE2 receptors and enters cells. The symptoms are cough, breathlessness, loss of taste/smell and X-ray evidence of infiltrates on chest imaging initially caused by oedema, and subsequently by a lymphocytic pneumonitis. Coagulopathy, thrombosis and hypotension occur. Worse disease occurs with age, obesity, ischaemic heart disease, hypertension and diabetes.These features may be due to abnormal activation of the contact system. This triggers coagulation and the kallikrein-kinin…
Antiviral peptides inhibiting the main protease of SARS-CoV-2 investigated by computational screening and in vitro protease assay - The main protease (Mpro) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) plays an important role in viral replication and transcription and received great attention as a vital target for drug/peptide development. Therapeutic agents such as small-molecule drugs or peptides that interact with the Cys-His present in the catalytic site of Mpro are an efficient way to inhibit the protease. Although several emergency-approved vaccines showed good efficacy and drastically dropped the…
Plant-Derived Natural Compounds as an Emerging Antiviral in Combating COVID-19 - Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a human virus that burst at Wuhan in China and spread quickly over the world, leading to millions of deaths globally. The journey of this deadly virus to different mutant strains is still ongoing. The plethora of drugs and vaccines have been tested to cope up this pandemic. The herbal plants and different spices have received great attention during pandemic, because of their anti-inflammatory, and immunomodulatory properties in…
Enumeration of olive derived lignan, pinoresinol for activity against recent Omicron variant spike protein for structure-based drug design, DFT, molecular dynamics simulations, and MMGBSA studies - The coronavirus disease 2019 (COVID-19) was first found in Wuhan, China, in December 2019. Because the virus spreads quickly, it quickly became a global worry. Coronaviridae is the family that contains both SARS-CoV-2 and the viruses that came before (i.e., MERS-CoV and SARS-CoV). Recent sources portray that the COVID-19 virus has affected 344,710,576 people worldwide and killed about 5,598,511 people in the last 2 years. The B.1.1.529 strain, later called “Omicron,” was named a Variant of…
Amplification of poly(I:C)-induced interleukin-6 production in human bronchial epithelial cells by priming with interferon-γ - Proinflammatory cytokine interleukin (IL)-6 was associated with disease severity in patients with COVID-19. The mechanism underlying the excessive IL-6 production by SARS-Cov-2 infection remains unclear. Respiratory viruses initially infect nasal or bronchial epithelial cells that produce various inflammatory mediators. Here, we show that pretreatment of human bronchial epithelial cells (NCl-H292) with interferon (IFN)-γ (10 ng/mL) markedly increased IL-6 production induced by the toll-like…
Diabetic individuals with COVID-19 exhibit reduced efficacy of gliptins in inhibiting dipeptidyl peptidase 4 (DPP4). A suggested explanation for increased COVID-19 susceptibility in patients with type 2 diabetes mellitus (T2DM) - AIMS: Dipeptidyl peptidase 4 (DPP4) has been proposed as a coreceptor for SARS-CoV-2 cellular entry. Considering that type 2 diabetes mellitus (T2DM) has been identified as the most important risk factor for SARS-CoV-2, and that gliptins (DPP4 inhibitors) are a prescribed diabetic treatment, this study aims to unravel the impact of DPP4 in the intersection of T2DM/COVID-19.
Engineering irradiated tumor-derived microparticles as personalized vaccines to enhance anti-tumor immunity - The inadequate activation of antigen-presenting cells, the entanglement of T cells, and the highly immunosuppressive conditions in the tumor microenvironment (TME) are important factors that limit the effectiveness of cancer vaccines. Studies show that a personalized and broad antigen repertoire fully activates anti-tumor immunity and that inhibiting the function of transforming growth factor (TGF)-β facilitates T cell migration. In our study, we introduce a vaccine strategy by engineering…
Willow (Salix spp.) bark hot water extracts inhibit both enveloped and non-enveloped viruses: study on its anti-coronavirus and anti-enterovirus activities - CONCLUSION: Salix spp. bark extracts contain several virucidal agents that are likely to act synergistically and directly on the viruses.
Unveiling the role of PUS7-mediated pseudouridylation in host protein interactions specific for the SARS-CoV-2 RNA genome - Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a positive single-stranded RNA virus, engages in complex interactions with host cell proteins throughout its life cycle. While these interactions enable the host to recognize and inhibit viral replication, they also facilitate essential viral processes such as transcription, translation, and replication. Many aspects of these virus-host interactions remain poorly understood. Here, we employed the catRAPID algorithm and utilized the…
Case report: Supratherapeutic tacrolimus concentrations with nirmatrelvir/ritonavir in a lung transplant patient: a case report using Rifampin for reversal - Paxlovid (nirmatrelvir/ritonavir) is an antiviral drug used to treat COVID-19, nirmatrelvir, a SARS-CoV-2 main protease inhibitor, works by inhibiting viral replication in the early stages, and ritonavir is a strong cytochrome P450 (CYP) 3A inhibitor that helps the nirmatrelvir reach and maintain the therapeutic concentrations. Paxlovid has a potential risk of drug interaction by elevating the plasma concentration of other drugs metabolized by CYP3A, like tacrolimus. This report examines the…
The spike protein of SARS-CoV-2 induces inflammation and EMT of lung epithelial cells and fibroblasts through the upregulation of GADD45A - Lung epithelial cells and fibroblasts poorly express angiotensin-converting enzyme 2, and the study aimed to investigate the role of the spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on inflammation and epithelial-mesenchymal transition (EMT) in two lung cell lines and to understand the potential mechanism. Lung epithelial cells (BEAS-2B) and fibroblasts (MRC-5) were treated with the spike protein, then inflammatory and EMT phenotypes were detected by…
Exploring Novel Vitamin K Derivatives with Anti-SARS-CoV-2 Activity - From our compound library of vitamin K derivatives, we found that some compounds exhibited anti-SARS-CoV-2 activity in VeroE6/TMPRSS2 cells. The common structure of these compounds was menaquinone-2 (MK-2) with either the m-methylphenyl or the 1-naphthyl group introduced at the end of the side chain. Therefore, new vitamin K derivatives having more potent anti-SARS-CoV-2 activity were explored by introducing various functional groups at the ω-position of the side chain. MK-2 derivatives with a…
The role of tocilizumab in the treatment of post-transfusion hyperhaemolysis - Hyperhaemolysis syndrome (HHS) is a serious complication of transfusion mostly reported in patients with sickle cell disease. HHS is characterised by the destruction of both donor and autologous red blood cells. Tocilizumab is a recombinant humanised monoclonal antibody that inhibits the binding of interleukin-6 and has been used in the treatment of severe/critical coronavirus disease 2019 infection but also some cases of HHS. We describe two further cases of HHS successfully treated with…
Immune responses and clinical outcomes following the third dose of SARS-CoV-2 mRNA-BNT162b2 vaccine in advanced breast cancer patients receiving targeted therapies: a prospective study - CONCLUSIONS: Our results confirm that the immune response to tozinameran is impaired by CDK4/6 inhibitors, increasing the odds of breakthrough infections despite the third vaccine dose. Current evidence recommends maintaining efforts to provide booster immunizations to the most vulnerable cancer patients, including those with advanced breast cancer undergoing CDK4/6 inhibition.